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SDR9C7 Catalyzes Critical Dehydrogenation of Acylceramides for Skin Barrier Formation

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SDR9C7 Catalyzes Critical Dehydrogenation of Acylceramides for Skin Barrier Formation SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation Takuya Takeichi, … , Alan R. Brash, Masashi Akiyama J Clin Invest. 2019. https://doi.org/10.1172/JCI130675. Research In-Press Preview Dermatology Graphical abstract Find the latest version: http://jci.me/130675/pdf 1 Takeichi et al. Research article SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation Takuya Takeichi1,*, Tetsuya Hirabayashi2, Yuki Miyasaka3, Akane Kawamoto4, Yusuke Okuno5, Shijima Taguchi6, Kana Tanahashi1, Chiaki Murase1, Hiroyuki Takama7, Kosei Tanaka8, William E. Boeglin9, M. Wade Calcutt10, Daisuke Watanabe7, Michihiro Kono1, Yoshinao Muro1, Junko Ishikawa4, Tamio Ohno3, Alan R. Brash9,* and Masashi Akiyama1,* 1Departments of Dermatology, 3Division of Experimental Animals, Nagoya University 2 Graduate School of Medicine, Nagoya 466-8550, Japan; Laboratory of Biomembrane, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; 4Biological Science Research Laboratories and 8Analytical Science Research Laboratories, Kao Corporation, Haga, Tochigi 321-3497, Japan; 5Medical Genomics Center, Nagoya University Hospital, Nagoya 466-8550, Japan; 6Division of Dermatology, Mito Kyodo General Hospital, Mito, Ibaraki 310-0015, Japan; 7Department of Dermatology, Aichi Medical University, Nagakute, Japan; 9Departments of Pharmacology and Biochemistry10 and the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, USA. *Correspondence: Takuya Takeichi, Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Telephone: 81-52-744-2314 Fax: 81-52-744-2318 E-mail: [email protected] Masashi Akiyama E-mail: [email protected] Alan R. Brash, Departments of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, USA. Telephone: 1-615-322-3015 E-mail: [email protected] 1 2 Takeichi et al. Running title: SDR9C7 is crucial for skin barrier formation Abbreviations: APCI, atmospheric pressure chemical ionization (mass spectrometry); ARCI, autosomal recessive congenital ichthyosis; C18:1-triol, 9,10,13-trihydroxy-11E- octadecenoic acid; CCE, cornified cell envelope; CLE, corneocyte lipid envelope; DEG, differentially expressed gene; eLOX3, epidermal lipoxygenase-3; EOS, esterified omega- hydroxy sphingosine; EpOH, epoxy-alcohol; HODE, hydroxy-octadecadienoic acid; KO, knockout; LC-MS, liquid chromatography-mass spectrometry; 12R-LOX, 12R- lipoxygenase; Me, methyl ester; NAD+ and NADH, oxidized and reduced forms of nicotinamide adenine dinucleotide, respectively; qPCR, quantitative PCR; RRR-EpOH, 9R,10R-trans-epoxy-11E-13R-hydroxy-octadecenoic acid; SDR9C7, short-chain dehydrogenase/reductase family 9C member 7; TEWL, trans-epidermal water loss; TLC, thin-layer chromatography; ULCFA; ultra-long-chain fatty acid; WT, wild-type 2 3 Takeichi et al. Abstract The corneocyte lipid envelope composed of covalently bound ceramides and fatty acids is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7 knockout model we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative LC- MS assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its non-enzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis. Brief summary SDR9C7, one of the ichthyosis-causative molecules, catalyzes dehydrogenation of acylceramide-epoxy-alcohol, and facilitates a critical coupling of ceramides to cornified cell envelope proteins in skin barrier formation. Keywords: ceramide, CerEOS, corneocyte lipid envelope, covalent protein binding, dehydrogenation, epoxy-enone, ichthyosis, lipoxygenase, SDR9C7, short-chain dehydrogenase/reductase, skin barrier, stratum corneum 3 4 Takeichi et al. Introduction During the evolutionary process, when our ancestors left the aquatic environment, our integument developed a robust protective structure in the uppermost epidermis, the “stratum corneum”, and adjusted to the dry environment on the ground (1). The water barrier property of the stratum corneum is achieved by a fusion of lipids and proteins in the terminally differentiated corneocytes of the outer epidermis; the cell membrane is replaced by a coat of cross-linked proteins (the cornified cell envelope, CCE), and multi- laminar lipid layers mainly composed of ceramides, cholesterol, and free fatty acids fill the space between the cells. Interfacing between the two on the outside surface of the CCE is a layer of covalently bound ceramides and fatty acids, the corneocyte lipid envelope (CLE) (2-4). The importance of the CLE to the integrity of the permeability barrier is known from its absence being a prime structural defect in many diseases of barrier function (4, 5). Among the epidermal ceramides, a key component is the ω-O- acylceramide CerEOS (Esterified Omega-hydroxy Sphingosine). Defects in genes involved in biosynthesis of CerEOS or its processing to form the CLE result in the severe skin disorder, autosomal recessive congenital ichthyosis (ARCI), characterized by dry skin, scaling, hyperkeratosis, and occasional erythroderma (6, 7). Moreover, alterations of epidermal lipid homeostasis, especially contents of CerEOS and other ceramides are linked to atopic dermatitis (8). Thus, abnormal metabolism of epidermal ceramides underlies the pathogenesis of various skin diseases associated with defective skin barrier function. The esterified component of CerEOS is the essential fatty acid linoleate (C18:2ω6), linked through an ester bond to the eponymous fatty acid omega-hydroxyl of EOS (9). Enzymatic oxidation of the linoleate ester in CerEOS by lipoxygenases (LOXs) is required for formation of the CLE (10, 11). Loss-of-function of 12R-lipoxygenase (12R-LOX) or epidermal lipoxygenase-3 (eLOX3) by gene mutations results in impaired permeability barrier function in patients with ARCI and in the corresponding knockout mice (12-14). The linoleate moiety of EOS cannot be replaced functionally by other fatty acids because they do not serve as a substrate for these epidermal LOXs. Accordingly, substitution of linoleate by oleate in CerEOS by prolonged intake of a diet lacking essential fatty acids impairs the normal formation of protein-bound ceramides (15), leading to an ichthyosis-like condition with dermatitis and increased transepidermal water loss (TEWL). The mechanism in which the CLE is constituted from oxidized EOS on the surface 4 5 Takeichi et al. of CCE has not been fully resolved. It has been assumed that an unidentified esterase/lipase de-esterifies the oxidized linoleate in EOS to generate free ω-hydroxy ceramide (CerOS) for covalent binding to the CCE, thus forming the CLE (4, 5, 10, 11, 16). Transglutaminase could catalyze the covalent attachment of the free ω-OH group to glutamate or glutamine residues of CCE proteins such as involucrin, periplakin, and envoplakin (17, 18). However, the transglutaminase(s) are not identified, and known gene knockouts do not exhibit the expected skin phenotype with absence of the CLE (19, 20). Furthermore, results inconsistent with the current line of thinking come from inactivation studies with PNPLA1, the gene that esterifies linoleate to CerOS, forming CerEOS (21- 25). In Pnpla1-deficient mice or patients with mutations in the PNPLA1 gene, the CLE is almost absent even though CerOS and its glucosylated form are highly accumulated (22, 24, 25). This suggests that the prerequisite for lipoxygenase-catalyzed oxidation of CerEOS is not in order to facilitate de-esterification of the linoleate moiety and produce CerOS, but rather has a different functional role during formation of the CLE. Herein we report new insights into skin barrier formation stemming from an understanding of the activities of a recently described ARCI gene, SDR9C7. SDR9C7 encodes a short chain dehydrogenase/reductase family 9C member 7 (SDR9C7) (26, 27), and is highly expressed in the epidermis (28). In 2016, two missense mutations in SDR9C7 were identified in patients with ARCI (29), and several more in 2018 (30). Our ultrastructural observations of the skin lesion of an ARCI patient with SDR9C7 mutations revealed disruption of the intercellular lipid layers in the stratum corneum (31). Now we have unraveled the pathomechanism and the enzymology of SDR9C7 through detailed structural and biochemical analyses
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